We hypothesize that chronic intraprostatic inflammation contributes to the development of prostate cancer. Chronic inflammation may serve as an initiator and/or promoter of prostate carcinogenesis as it does in infection-associated liver and stomach cancer and in colon cancer in inflammatory bowel disease. Indeed, regions of atrophy showing hyperproliferation and inflammation, called proliferative inflammatory atrophy (PIA) lesions, are common in the prostate. These lesions may be regenerative and may be the result of response to infection or cell trauma due to oxidant damage or hypoxia. To address this hypothesis, we propose to evaluate the association of tissue, circulating, and genetic markers of inflammation, its sources, or sequelae with prostate cancer. Prostate cancer cases and age frequency-matched controls who were negative on an end-of-study biopsy will be selected from among participants in the Prostate Cancer Prevention Trial (PCPT). In biopsy sections from 400 cases and 400 controls, we will determine the prevalence, extent, and biological characteristics of inflammation and atrophy using immunohistochemistry or FISH and image analysis. We will detect antibodies against 5 infectious agents (e.g., Chlamydia trachomatous, Trichomonas vaginalis) by ELISA in serum from 600 cases and 600 controls. We will genotype 1800 cases and 1800 controls for germline polymorphisms in 12 genes involved in the innate and adaptive immune response to infection and tissue damage (e.g., TLR-4, IFNy,IL-10) using MALDI-TOF. We will use logistic regression to estimate the odds ratios of prostate cancer and high-grade disease. Jointly with the other Projects, we will test whether the associations vary by exposure to factors that may alter adverse effects of inflammation, including the PCPT study drug finasteride, levels of serum antioxidants, sex steroid hormones, and growth factors. Given that inflammation is a clear target for intervention, we anticipate that the proposed work will have important implications for prostate cancer prevention. The revised Project addresses all reviewer concerns, including those for new preliminary data on the association of inflammation with prostate cancer in the PCPT and additional immunology expertise.